Abstract P1-11-06: Multi-omics profiling of HER2-low breast cancer reveals clinically relevant subgroups and therapeutic pathways

Abstract

Abstract The current HER2 testing algorithm can distinguish tumors that are completely negative for HER2 (IHC 0, HER2-zero) from HER2-low tumors [low (IHC 1+) or moderate expression (IHC 2+, ISH-)]. Because HER2-zero cases have often been combined with HER2-low cases, the clinical and biological understanding of HER2-low tumors is limited. To provide complementary information and shed light on the molecular characteristics and therapeutic insights of HER2-low breast cancer, we performed this multi-omics study of hormone receptor (HR)-negative and HER2-low breast cancer, also known as HER2-low triple-negative breast cancer (TNBC), and identified three subgroups: basal-like (BSL), receptor tyrosine kinase relevant (TKR), and mesenchymal stem-like (MSL). These three subgroups had distinct features and potential therapeutic targets and were validated in external datasets. Interestingly, the TKR subgroup (which exists in both HR-positive and HR-negative breast cancer) had activated HER2 and downstream MAPK signaling. In vitro and in vivo patient-derived xenograft experiments revealed that pretreatment with tyrosine kinase inhibitor (Lapatinib or Tucatinib) could inhibit HER2-signaling and induce accumulated expression of nonfunctional HER2 via a feedback loop, resulting in increased sensitivity to sequential HER2-targeting antibody-drug conjugate DS-8201. Our findings identify clinically relevant subgroups and provide potential therapeutic strategies for the previously targetless HER2-low TNBC subtype. GRAPH ABSTRACT Highlights of characteristics of HR-negative and HER2-low breast cancer subgroups Table S1. Highlights of characteristics of HR-negative and HER2-low breast cancer subgroups. Citation Format: Lie Chen, Cui-Cui Liu, Jing-Yu Ge, Zhi-Ming Shao, Ke-da Yu. Multi-omics profiling of HER2-low breast cancer reveals clinically relevant subgroups and therapeutic pathways [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-06.